Precision medicine at UNC: Looking for cancer-driving gene mutations across cancershttp://unclineberger.org/news/tumor-genetics
UNC Lineberger will be enrolling patients into a new, national clinical trial, known as NCI-MATCH, that will group patients based on the genetics of their tumors as opposed to where their cancer is located. The new initiative will test more than 20 drugs or drug combinations targeting specific genetic mutations.UNC Lineberger Comprehensive Cancer Center researchers are leading an emerging scientific approach to cancer treatment that is building on advances in genetic sequencing. In this investigational approach to cancer treatment, patients are treated based on the genetic mutations found in their cancer.

Cancer center oncologists have been designing and enrolling patients in clinical trials known as “basket trials" to test this approach. In these basket trials, patients are selected for treatment for targeted drugs based on whether they have certain mutations or molecular alterations. The strategy represents a shift away from treating patients based on where their tumors originated, as patients are eligible for a trial if their tumors are found to have a specific mutation– regardless of where their cancer was first diagnosed in the body.

“Historically, we looked to treat cancers based on where they started in the patient,” saidJuneko Grilley-Olson, MD, a UNC Lineberger member and medical oncologist. “But now, we understand that sometimes molecular changes found across different types of cancers leads to a more sophisticated way to treat them.”

This approach will be tested in a new, nationwide clinical trial co-developed by the National Cancer Institute. For this trial, known as the Molecular Analysis for Therapeutic Choice Trial, or NCI MATCH trial, several thousand people are expected to be screened for molecular alterations. About 1,000 patients are expected to be enrolled, and more than 20 drugs or drug combinations targeting a specific genetic mutation are expected to be tested, according to the NCI. Enrollment is expected to begin in July for the trial's first 10 arms. Grilley-Olson is co-chair for a future trial am that's planned to study the use of drugs targeting the phosphoinositide 3-kinase (PI3K) enzyme pathway.

“NCI‐MATCH is a unique, ground‐breaking trial,” said Doug Lowy, MD, NCI acting director, in a prepared statement in a release by the NCI. "It is the first study in oncology that incorporates all of the tenets of precision medicine. There are no other cancer clinical trials of this size and scope that truly bring the promise of targeted treatment to patients whose cancers have specific genetic abnormalities. It holds the potential to transform cancer care.”

Already, UNC has led a variety of basket trials outside of NCI-MATCH, Grilley-Olson said, including trials with pharmaceutical companies. There are two separate industry-sponsored trials currently ongoing at UNC, she said, including one trial that will test a handful of drugs shown to target four different mutations, including one for people with mutations in the BRAF gene. Drugs have been approved for people with advanced melanoma with a specific BRAF mutation, but the new trial will test the drug in patients with other types of cancer as well.

“Remarkable” advances in genetic sequencing, as well as in the understanding of cancer have made such a treatment approach possible, Grilley-Olson said. Cancer is now understood fundamentally as a genetic disease, with molecular alterations or abnormalities driving the uncontrolled growth of cells. The sequencing of an individual patient’s tumors is becoming standard of care. Patients at the N.C. Cancer Hospital are having their tumors sequenced as standard of care in a state-of-the-art pathology facility, or when further analysis is needed, as part of a clinical trial called UNCseq.

“Those results can be placed in the patient’s medical record, thus enabling any treating physician to know what alterations may be driving the cancer, and thereby being better able to identify patients for trials such as these basket trials,” Grilley-Olson said. The new approach to treatment will hopefully open doors for possible treatments for patients with diseases that have otherwise limited options and allow researchers to identify cancer types that may or may not be responsive to these drugs.

]]>No publisher2015cancer geneticsgeneticsclinical trials2015/06/10 10:45:00 GMT-4News ItemUNC Lineberger breast cancer researcher wins ASCO foundation granthttp://unclineberger.org/news/asco-reeder-hayes
Katherine Reeder-Hayes, MD, MBA, Msc, a UNC Lineberger member and a clinical assistant professor in the University of North Carolina School of Medicine, won a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology. She was one of 11 clinical investigators chosen to receive the three-year award, which goes to researcher-physicians to help them build independent clinical research programs.A UNC Lineberger Comprehensive Cancer Center breast cancer physician-researcher has won a $200,000 award from the Conquer Cancer Foundation to study how breast cancer patients and their doctors are using genetic information to make treatment decisions.

Katherine Reeder-Hayes, MD, MBA, Msc, a UNC Lineberger member and a clinical assistant professor in the University of North Carolina School of Medicine, won a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology. She was one of 11 clinical investigators chosen to receive the three-year award, which goes to researcher-physicians to help them build independent clinical research programs.

Specifically, Reeder-Hayes said she plans to use the award to study how real-world patients are using a particular gene expression profiling test that’s designed to help doctors and patients make decisions about whether patients will benefit from chemotherapy.

In the study, she and her collaborators plan to use data on a diverse population of cancer patients across North Carolina to look at how uptake of the test varies by factors like age, race and provider location. They also plan to compare the treatment plans for patients who got tested and patients who didn’t in order to understand the impact of testing on chemotherapy use. And finally, they will measure breast cancer recurrence and survival among tested and untested women.

“We’re interested in understanding what factors are driving decisions about whether women get the gene expression profiling test or not, and whether there differences by age, race, by where they live and get their care,” she said. “We then want to follow the story to see whether they get chemotherapy or not, and then to see whether the disease comes back.”

The research effort to understand the value and use of genomic information in breast cancer treatment will be cutting-edge, said Ethan Basch, MD, MSc, director of the Cancer Outcomes Research Program at UNC Lineberger, an associate professor in the UNC School of Medicine Division of Hematology and Oncology, and Reeder-Hayes’ mentor for the award.

Reeder-Hayes will be recognized with other award recipients during the Grants and Awards Ceremony at the 2015 ASCO annual meeting, which is being held through Tuesday in Chicago.

Other UNC investigators have also been recognized by the foundation.

Second-year fellow Adam Belanger, MD, received the Conquer Cancer Foundation of ASCO's Young Investigator Award. The one-year grant of $50,000 provides research funding to promising physicians to support the transition from fellowship to faculty appointment, encourage continued interest in clinical cancer research and assist them in their careers as both physicians and researchers.

]]>No publisher2015cancer geneticsbreast cancercancer disparities2015/06/02 09:30:00 GMT-4News ItemA new era for genetic interpretationhttp://unclineberger.org/news/new-era-for-genetic-interpretation
UNC Lineberger researchers are collaborating through the ClinGen consortium - a program launched to evaluate the clinical relevance of genetic variants - to help physicians make predictions about an individual’s risk of disease, develop more accurate clinical trials and design individualized treatments and care for patients.
Millions of genetic variants have been discovered in the last 25 years, but interpreting the clinical impact of the differences in a person’s genome remains a major bottleneck in genomic medicine. In a paper published today in The New England Journal of Medicine, a consortium including investigators from the University of North Carolina School of Medicine and UNC Lineberger Comprehensive Cancer Center present ClinGen, a program launched to evaluate the clinical relevance of genetic variants for use in precision medicine and research.

“Sequencing has revealed that there are potentially several million genetic variants per person,” said Jonathan Berg, MD, PhD, a UNC Lineberger member, an assistant professor in the UNC School of Medicine Department of Genetics and this year's ClinGen steering committee chair. “Right now there is a certain degree to which we can infer what those variants do, but most of them remain really beyond our understanding of how they are affecting human health, if at all. Through ClinGen, we’re working to evaluate the clinical relevance of genes and variants, and to provide a public database so that labs and clinicians will have a resource that they can go to as a way to understand their patients’ genetic testing results.”

Clinicians and researchers hope to use information about genetic variants not only to make predictions about an individual’s risk of disease, but also to develop more accurate clinical trials and better, tailored treatments and care for patients. However, labs and clinicians may interpret the same variant differently.

Part of ClinGen’s mission is to resolve these differences. Members of ClinGen are actively working with laboratories around the world to help them share their data and implement standards developed by the American College of Medical Genetics and Genomics for interpreting genetic variants, with the goal of resolving interpretation differences.

An integral part of the ClinGen project is ClinVar: a database launched in April of 2013 that currently contains more than 170,000 variant submissions from laboratories around the world. The database is publicly accessible, meaning that clinicians and researchers as well as patients can look up information to find out what is known about a specific genetic variant, and the site gets an average of 5,000 hits per day. The collaborators are working to enhance the number and quality of submissions to the ClinVar database, Berg said.

In addition, ClinGen has formed expert working groups to interpret the strength of gene-disease relationships, resolve differences in the interpretation of variants’ clinical significance found in ClinVar, and move variants into the category of “expert panel reviewed” so they can be used more confidently in clinical decision-making. Berg is a co-principal investigator on the grant awarded to UNC and several partners to support the coordination of the clinical domain working groups. He said the groups are looking at variants that could play a role in a range of diseases including pediatric metabolic disorders, cardiovascular conditions and inherited types of cancer.

“UNC’s main role in ClinGen is, in conjunction with several partners, to coordinate the clinical domain working groups to essentially do the work of curating genes and variants,” Berg said.

Another key aspect of the project will be to develop an informatics system to help the researchers review the genetic variants, Berg said. One of the project goals is to develop machine-learning algorithms to improve the interpretation of the variants.

“Our model works a little like Wikipedia: anyone can submit variants and interpretations to the database to rapidly enable shared resources, but that content is later curated by an expert group to standardize quality,” said Heidi Rehm, PhD, associate professor of pathology at Brigham and Women’s Hospital (BWH) and director of the Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine. Investigators from Brigham and Women’s Hospital and Partners HealthCare are also involved in the ClinGen consortium.

ClinGen has also set up a patient portal where those who are interested in sharing their genetic data and health information can register. Known as GenomeConnect, the portal connects researchers, clinicians and patients to learn about the effects of genetics on human health and disease. Patients who have had or are considering having genetic testing can share their results and take surveys to share information about their health. De-identified information will be transferred to ClinVar and other ClinGen resources for advancing genomic knowledge and participants will receive updates when there are opportunities to connect with other participants who share the same condition, gene or genetic variant. Patients can access GenomeConnect to join, and ClinVar to search for genetic variants.

ClinGen is funded by the National Human Genome Research Institute, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute (U41 HG006834, U01 HG007436, U01 HG007437, HHSN261200800001E). ClinVar is supported by the Intramural Research Program of the NIH, National Library of Medicine.

In addition to Berg, the co-principal investigators of the grant awarded to UNC and its partners include James P. Evans, MD, PhD, the UNC School of Medicine Bryson Distinguished Professor of Genetics and Medicine and a UNC Lineberger member, Michael Watson, PhD, executive director of the American College of Medical Genetics and David Ledbetter, PhD, executive vice president and chief scientific officer of Geisinger Health System.

About UNC Lineberger

One of only 41 NCI-designated comprehensive cancer centers, the University of North Carolina Lineberger Comprehensive Cancer Center brings together some of the most exceptional physicians and scientists in the country to investigate and improve the prevention, early detection and treatment of cancer. With research that spans the spectrum from the laboratory to the bedside to the community, UNC Lineberger faculty work to understand the causes of cancer at the genetic and environmental levels, to conduct groundbreaking laboratory research, and to translate findings into pioneering and innovative clinical trials. For more information, please visit www.unclineberger.org.

About Brigham and Women’s Hospital

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in Massachusetts and employs nearly 15,000 people. The Brigham’s medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation’s first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials group. For more information, resources and to follow us on social media, please visit BWH’s online newsroom.

]]>No publisher2015cancer geneticsgenetics2015/05/27 09:30:00 GMT-4News ItemPartnering with IBM and Watson to accelerate DNA analysis and inform personalized treatmenthttp://unclineberger.org/news/partnering-with-ibm-and-watson-to-accelerate-dna-analysis-and-inform-personalized-treatment
UNC Lineberger will be one of more than a dozen leading cancer centers tapping IBM's Watson to accelerate DNA analysis and inform personalized treatment options for patients. The project is part of IBM’s broader Watson Health initiative to advance patient-centered care and improve health.IBM Watson Health (NYSE: IBM) today announced that it is collaborating with more than a dozen leading cancer institutes, including UNC Lineberger, to accelerate the ability of clinicians to identify and personalize treatment options for their patients. The institutes will apply Watson's advanced cognitive capabilities to reduce from weeks to minutes the ability to translate DNA insights, understand a person’s genetic profile and gather relevant information from medical literature to personalize treatment options. The project is part of IBM’s broader Watson Health initiative to advance patient-centered care and improve health.

The collaborations will enable clinicians to use Watson with a much broader set of patients by the end of 2015, and will accelerate the promise of personalized medicine for cancer patients everywhere. In addition to UNC Lineberger, Ann & Robert H Lurie Children’s Hospital of Chicago, BC Cancer Agency, City of Hope, Cleveland Clinic, Duke Cancer Institute, Fred & Pamela Buffett Cancer Center in Omaha, Nebraska, McDonnell Genome Institute at Washington University in St. Louis, New York Genome Center, Sanford Health, University of Kansas Cancer Center, University of Southern California Center for Applied Molecular Medicine, University of Washington Medical Center, and Yale Cancer Center are among the first to participate in the project. As participating institutions use Watson to assist clinicians in identifying cancer-causing mutations, Watson’s rationale and insights will continually improve, providing the latest combined wisdom of the world’s leading cancer institutes for oncologists.

“We are partnering with IBM in an effort to solve this decision problem with the help of cognitive technology and to improve the decisions we make with our patients to maximize their chance for cure.” - Dr. Ned Sharpless

Most of the 1.6 million Americans who are diagnosed with cancer each year receive surgery, chemotherapy or radiation treatment. Yet when these standard treatments fail and as genetic sequencing becomes increasingly accessible and affordable, some patients are beginning to benefit from treatments that target their specific cancer-causing genetic mutations. However, the process is time-consuming and requires clinicians to sift through and reconcile a deluge of genetic information – for example a single patient’s genome represents more than 100 gigabytes of data – in addition to health information such as electronic medical records, journal studies, and clinical trial information.

Watson can help clinicians quickly sift through this data and provide comprehensive insights on cancer-causing mutations and medical literature that is potentially relevant. It typically takes weeks for clinicians to analyze each mutation and the available medical literature to then identify tailored treatment options for a patient. Watson completes the genetic material and medical literature review process in only a few minutes, producing a report and data visualization of the patient’s case, and evidence-based insights on potential drugs that may be relevant to an individual patient’s unique DNA profile identified in the medical literature. The clinician can then evaluate the evidence to determine whether a targeted therapy may be more effective than standard care for the patient.

“Determining the right drug combination for an advanced cancer patient is alarmingly difficult, requiring a complex analysis of different sources of Big Data that integrates rapidly emerging clinical trial information with personalized gene sequencing,” said Norman Sharpless, MD, director, UNC Lineberger. “We are partnering with IBM in an effort to solve this decision problem with the help of cognitive technology and to improve the decisions we make with our patients to maximize their chance for cure.”

In the initial phase of the program, participating organizations will apply Watson to the DNA data of patients who are battling all types of cancer, including lymphoma, melanoma, pancreatic, ovarian, brain, lung, breast and colorectal cancer.

]]>No publisher2015genomicscancer geneticsgenetics2015/05/05 00:00:00 GMT-4News ItemUNC researchers create DNA repair map of the entire human genomehttp://unclineberger.org/news/unc-researchers-create-dna-repair-map-of-the-entire-human-genome
The new experimental assay can help scientists find the precise locations of repair of DNA damage caused by UV radiation and common chemotherapies. The invention could lead to better cancer drugs or improvements in the potency of existing ones.When the common chemotherapy drugs cisplatin or oxaliplatin hit cancer cells, they damage DNA so that the cells can’t replicate. But the cells have ways to repair the DNA. The cancer drugs aren’t as effective as patients need. Researchers at the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center have developed a method for finding where this DNA repair happens throughout all of human DNA.

The findings, published in the journal Genes & Development, offers scientists a potential way to find and target the proteins cancer cells use to circumnavigate therapy. The benefit of this new method could be more effective and better tolerated classes of cancer therapeutics.

The research, led by Aziz Sancar, MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and Biophysics, marks the first time scientists have been able to map the repair of DNA damage over the entire human genome.

“Now we can say to a fellow scientist, ‘tell us the gene you’re interested in or any spot on the genome, and we’ll tell you how it is repaired,’” said Sancar, co-senior author and member of the UNC Lineberger Comprehensive Cancer Center. “Out of six billion base pairs, pick out a spot and we’ll tell you how it is repaired.”

When DNA is damaged, cells use many enzymes to cut the strand of DNA and excise the damaged fragment. Then, other enzymes repair the original DNA so that the cells can function properly. Previously, Sancar’s lab used purified enzymes to discover how this process happens in DNA damaged by UV irradiation and by chemotherapeutic drugs such as cisplatin and oxaliplatin.

In recent years, Michael Kemp, PhD, in Sancar’s team found that a particular protein called TFIIH bound tightly to the excised damaged DNA fragment in the test tube. But for this information to be truly useful to biomedical researchers, the experiment needed to be replicated in human cells. Extracting a stable TFIIH-DNA fragment proved difficult. Not until postdoctoral fellow Jinchuan Hu, PhD, co-first author on the Genes & Development paper, joined Sancar’s lab could Sancar’s team accomplish the task.

Through a series of sophisticated experiments with human skin cells, Hu exposed the cells to ultraviolet radiation and used an antibody against the enzyme TFIIH to isolate the enzyme complex with the excised DNA damage. Then he created experimental techniques to pull the enzyme – as well as the excised DNA fragment it was bound to – from the cells.

The fragment was stable enough for Sancar’s lab to sequence it. Then, Sheera Adar, PhD, fellow postdoc and paper co-first author, and Jason Lieb, PhD, co-senior investigator of the study, used their expertise in computational biology to analyze where the DNA repair happened throughout the entire genome and thus generate a human genome repair map for the first time.

Because UV radiation and common chemotherapy drugs such as cisplatin cause DNA damage in similar ways, Sancar’s team is now using their new DNA excision repair method – called XR-Seq – to study cells affected by cisplatin. They also hope to use it to study the biochemical reactions in animal models with the goal of finding the specific mechanisms that allow cancer cells to repair DNA damage to survive.

“Cisplatin is an old drug,” Adar said. “Right now, it’s used with other drugs as a combination therapy. We know these drugs make cancer cells more sensitive to cisplatin. But we don’t really know how they do this. We now have an assay to find out how the cells’ DNA is being repaired. Our goal is to make cancer cells even more sensitive to existing drugs to help patients.”

The research also revealed that parts of the genome scientists previously thought did very little are actually part of this repair process.

On chromosomes, DNA forms genes that create proteins – the building blocks of life. Between these genes, there are DNA sequences – simple bits of genetic information.

“People have thought that this DNA didn’t do anything,” Adar said. “But it turns out that proteins bind to these other DNA sequences, and this affects other nearby or far away genes. Our analysis shows that these DNA regulatory sequences are also being repaired. So, if they’re being repaired, then they’re likely important. And now we can find their locations throughout the genome.”

Other authors on the Genes & Development paper are Christopher Selby, PhD, a research instructor in the Sancar lab, and Jason Lieb, PhD, a former UNC researcher who is now a professor of human genetics at the University of Chicago.

]]>No publisher2015genomicscancer geneticsgenetics2015/05/01 10:20:00 GMT-4News ItemRoger Johnsonhttp://unclineberger.org/patientstories/patient-stories/bladder-cancer/roger-johnson
Siler City native Roger Johnson knows the value of personalized medicine. After being diagnosed with bladder cancer in 2013, physicians at UNC sequenced his tumor to better understand the genetics driving his cancer.A native of Siler City, Roger Johnson has lived in North Carolina his entire life.

“I lived in Asheboro for a good bit too,” said Johnson. “Guess how many times I went to the zoo? Twice.”

Currently living in Carrboro, Johnson enjoys meeting all different types of people. Something he was able to do while working for 12 years at Carrboro’s small business The Ink Spot. It was during his time working there that he started to notice alarming health issues.

Following a series of tests at UNC Lineberger, Roger found out he was diagnosed with bladder cancer in February 2013.

“It was hard, it was really hard,” said Johnson.

Under the care of UNC Lineberger’s Dr. William Kim, associate professor in the UNC division of hematology and oncology and Dr. Michael Woods, associate professor of urology, Roger immediately began a treatment plan included several rounds of chemotherapy and the surgical removal of his bladder.

Roger’s tumor was sequenced through a clinical program at UNC Lineberger known as UNCseq, where patients tumors are sequenced to better understand their genetic makeup and in particular the mutations that are driving the cancer.

“This is the very definition of personalized medicine,” said Dr. Kim.

As a result of the genetic sequencing, Dr. Kim was able to determine that Roger’s cancer could possibly respond well to Afinitor, a treatment that is currently FDA approved for and in widespread use in kidney and breast cancer but not currently used in treatment of bladder cancer. But given the genetic similarities of the cancers, there was hope Roger’s bladder cancer would response favorably.

Dr. Kim was able to secure an insurance petition in order to get Roger access to the treatment, and he underwent 10 months on the therapy. Roger responded very well to the treatment, but another, more promising option then opened up.

“I knew there was a cancer immunotherapy trial about to open, and Roger would be an ideal candidate for the trial,” recalled Dr. Kim. The trial is testing an antibody designed to interfere with a protein called PD-L1 that is expressed on tumor cells. By inhibiting PD-L1, the immunotherapy drug may enable the activation of cancer fighting T cells, restoring their ability to effectively detect and attack the tumor.

The trial offered new hope for Roger, but would require him to go off of the Afinitor therapy.

“Dr. Kim prepared me that the transition would be hard, and it was,” said Roger. Between the therapies, Roger experiences severe pain and was even confined to a wheelchair. But, Roger remained hopeful the new therapy would pay off.

Roger responded almost immediately to the new immunotherapy treatment, improving his overall quality of life and slowing the progression of his cancer.

“I was coming into clinic in a wheelchair,” said Johnson. “And now I can walk. This has made a huge difference for me.”

Roger looks forward to getting back to meeting people and living life to the fullest.

“Everyone should take every day they are given and be thankful for it. I know I do.” says Johnson.

]]>No publisherpatient storiesbladder cancerimmunotherapycancer geneticsuncseq2015/04/23 16:05:00 GMT-4News ItemClinical Research Forum selects genomic analysis as top 10 research achievement http://unclineberger.org/news/clinical-research-forum-selects-genetic-analysis-study-as-top-10-research-achievement
A cancer genomics study led by UNC Lineberger researchers and other scientists involved in The Cancer Genome Atlas (TCGA) project, a National Cancer Institute and National Human Genome Research Institute-backed effort to create a comprehensive atlas of the genetic changes in cancer, was selected as one of the top 10 clinical research achievements of the year. The project characterized molecular changes in 12 different cancers and revealed a new approach to classifying cancers.

UNC Lineberger Comprehensive Cancer Center researchers played leading roles in a cross-cancer genomics study that has been selected as one of the nation’s top 10 research achievements of the year.

In findings published in the journal Cell in August of 2014, researchers with The Cancer Genome Atlas network revealed a new mechanism for classifying cancers. The project was led by UNC Lineberger researchers along with scientists from other project sites collaborating as part of TCGA, a National Cancer Institute and National Human Genome Research Institute-backed effort to create a comprehensive atlas of the genetic changes in cancer.

The study was selected as one of the year’s 10 most outstanding research papers by the Clinical Research Forum. The awardees were recognized April 16 during the forum’s fourth annual awards ceremony in Washington D.C.

“I applaud the researchers recognized for their groundbreaking clinical research that will advance new treatments to reduce suffering and bring hope to millions of people,” said NIH Director Dr. Francis S. Collins, M.D., Ph.D. “And I’m especially proud that NIH funding makes these advances possible.”

The 10 winning papers were chosen based on their degree of innovation from a pool of more than 50 nominations from 30 research and academic health centers nationwide.

The forum and its supporters believe these papers represent the best and brightest work in the field, and will lead to advancements in medicine that will change lives and patient outcomes worldwide.

In the award-winning TCGA pan-cancer study, researchers analyzed more than 3,500 samples from 12 different cancer types.

Part of what made the study unique, said Charles M. Perou, PhD, a UNC Lineberger member, professor of genetics, pathology and laboratory medicine at the UNC School of Medicine and a co-corresponding author of the paper, was that the researchers analyzed multiple genomic characteristics of the tumors. For example, they analyzed both the patterns in the tumors’ DNA, as well as in the RNA, which is the genetic code that carries instruction from DNA for making proteins.

“What set the TCGA project apart from similar genomic projects is that we actually had six different, very diverse and broad-reaching genome analysis technologies that we could use to study tumors’ molecular characteristics,” Perou said.

The study’s analysis found that the samples divided into 11 main groups, with some cancers from the same tissue of origin breaking into different groups, and others cancers from different tissue origin sites converging into a single group.

Katherine Hoadley, PhD, research assistant professor in genetics and a co-first author of the paper, said the findings suggest that tissue of origin may not always be as useful for classifying cancers as the type of cell from where the cancer originated. She also said the findings could have implications for treatment.

“We found about 10 percent of samples probably should not have been classified based on tumor site alone, suggesting that the treatment decisions might have been different for that percentage of patients that did not classify based on tissue type alone,” she said.

The Clinical Research Forum advocates for increased respect for the field, which members hope will translate to sustained financial support from the NIH, academia, foundations and other donors.

About the Clinical Research ForumFormed in 1996, the Clinical Research Forum convenes annually to allow industry leaders to discuss issues facing the field, best practices, and promote understanding and support for clinical research and its impact on health and healthcare. Through its activities, the Forum has increasingly played a national advocacy role in supporting broader interests and needs of clinical research. You can find more information at www.clinicalresearchforum.org.

]]>No publishercancer geneticsimmunologytcgaimmunotherapy20152015/04/20 10:05:00 GMT-4News ItemCancer genetics the focus of UNC Lineberger symposium http://unclineberger.org/news/cancer-genetics-the-focus-of-39th-unc-lineberger-symposium
UNC Lineberger's 39th annual scientific symposium was held April 8-9 at the William and Ida Friday Center for Continuing Education in Chapel Hill.Researchers working to uncover the genetic causes of cancer convened at UNC Lineberger Comprehensive Cancer Center’s 39th annual symposium April 8-9, sharing strides made to translate those findings into the clinic.

More than 400 people attended the 39th annual event held April 8-9 at the William and Ida Friday Center for Continuing Education in Chapel Hill. Researchers from institutions around the country and from the United Kingdom presented findings of genomic abnormalities in a variety of cancers including acute myeloid leukemia, breast cancer, kidney cancer, bladder cancer, melanoma, lymphoma and lung cancer.

Co-organizer Charles M. Perou, PhD, a UNC Lineberger member and professor of genetics, pathology and laboratory medicine at the UNC School of Medicine, argued that we now know the genetic cause of a particularly aggressive form of breast cancer known as triple negative breast cancer. Triple negative breast cancer would be tied for fifth in deaths of U.S. women per year if it were its own disease, Perou said. A national effort to characterize the molecular alterations in cancer known as The Cancer Genome Atlas project found that for the basal-like breast cancer subtype, there is a surprisingly short list of significantly mutated genes, but a high rate of mutations in the TP53 gene, he said.

“I’ll argue that we know the genetic causes of triple negative cancer,” Perou said. However, even with this knowledge in hand, “there’s still a great need to come up with therapies for the triple negative type of breast cancer.”

A number of the symposium speakers are actively involved in The Cancer Genome Atlas project (TCGA), which is a joint effort of the National Cancer Institute and National Human Genome Research Institute. Research institutions, including UNC, worked collaboratively as part of the project to map out the molecular characteristics of about 30 cancer types.

“(We) have generated this astounding resource, really, for cancer genomics, genetics, and now our challenge is to translate this into changes and improvements in clinical care,” Perou said of the results of TCGA so far. While he said the production side of the effort is largely finished, the analysis of the data generated from it is ongoing.

Elaine Mardis, PhD, a professor at The Genome Institute at the Washington University School of Medicine, described findings of a TCGA study that sought to characterize the molecular changes in 200 acute myeloid leukemia samples. They found that average number of mutated genes in any one sample was less than 15, she said.

Mardis described efforts to translate genomic findings into the clinic. She said the goal is to compare mutations in samples taken at diagnosis to mutations in samples 30 days after chemotherapy in order to be able to better predict which patients might relapse or who should be treated with additional therapies.

In addition, she described a research effort to use genomics to help identify mutations in order to develop a vaccine for advanced melanoma.

“(The translation) of cancer genomics – especially coming out of these large-scale studies like TCGA – is really under way,” she said.

William Y. Kim, MD, a UNC Lineberger member and an associate professor at the UNC School of Medicine, spoke on UNC’s findings of molecular subtypes of bladder cancer. Kimryn Rathmell, MD, PhD, spoke on molecular characteristics of renal cell carcinoma, a kidney cancer. A major finding of one TCGA analysis was that different subtypes of renal cell carcinoma are “night and day very different cancers,” Rathmell said, based on their molecular characteristics. “Renal cell carcinomas are a group of highly distinct, unrelated diseases,” she said.

Co-organizer D. Neil Hayes, MD, MPH, a UNC Lineberger member and an associate professor of clinical research in hematology and oncology at the UNC School of Medicine, spoke about a clinical trial at UNC that uses DNA sequencing to identify potential molecular markers in a patient’s tumor. The idea is to use the results of those tests to provide an individualized treatment protocol that directly targets the genetic alterations.

Fifty-five percent of 770 enrolled patients who have seen results from the trial so far were recognized to have an actionable mutation, Hayes said. He described successes and challenges seen so far of the in translating those findings into clinical practice, including access issues to the drugs associated with the actionable treatment.

Gordon B. Mills, chair of the Department of Systems Biology at The University of Texas MD Anderson Cancer Center in Houston, also spoke on an investigational program at MD Anderson to sequence cancer patients’ tumors to find actionable treatments for them. Mills said that we can now characterize patients’ cancers in a “breadth and depth” not thought possible before.

Other symposium speakers included Laura van’t Veer, PhD, Breast Oncology Program leader and associate director of applied genomics at the UCSF Helen Diller Family Comprehensive Cancer Center; Matthew Ellis, MD, director of the Lester and Sue Smith Breast Center at Baylor College of Medicine; Jason Carroll of the Cambridge Research Institute; Stephen Chanock, MD, director of the National Cancer Institute Division of Cancer Epidemiology & Genetics; Jennifer Grandis, MD, the University of California San Francisco associate vice chancellor of clinical and translational research; Matt Wilkerson, PhD, a UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Genetics; Max Wallace, CEO of Accelerate Brain Cancer Cure; Louis Staudt, MD, PhD, co-chief of the Lymphoid Malignancies Branch at the National Cancer Institute; Richard Gibbs, PhD, chair and professor of molecular and human genetics at the Baylor College of Medicine; Dmitry Gordenin, Ph.D., the head of the Mechanism of Genome Dynamics Group at the NIEHS, Josh Stuart, associate director of the UC Santa Cruz Center for Biomolecular Science & Engineering for Cancer and Stem Cell Genomics; and Matthew Meyerson, MD, PhD, professor of Pathology at the Harvard Medical School.

Support from the symposium was provided by the National Institutes of Environmental Health Sciences, Agilent Inc., Accelerate Brain Cancer Cure, Illumina, Foundation Medicine, Burroughs Wellcome Fund, Cell Signaling Technology, GeneCentric, New England BioLabs, and the Hamner Institute for Health Sciences.

]]>No publishercancer geneticsimmunologytcgaimmunotherapygenetics2015/04/10 14:50:00 GMT-4News ItemResearchers find new approach to treat drug-resistant HER2-positive breast cancer http://unclineberger.org/news/researchers-find-new-approach-to-treat-drug-resistant-her2-positive-breast-cancer
Using human cancer cell lines, UNC scientists identified various ways that HER2-positive breast cancer tumors resist therapy, and they discovered a potential combination therapy to overcome multiple mechanisms of resistance and kill cancer cells.Resistance to therapy is a major problem in the cancer field. Even when a treatment initially works, the tumors often find ways around the therapy. Using human cell lines of the HER2-positive breast cancer subtype, researchers from the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center have detailed the surprising ways in which resistance manifests and how to defeat it before it happens.

The discovery, published today in the journal CELL Reports, provides the experimental evidence for the potential development of a novel combination therapy for HER2-positive breast cancer. The combination includes the FDA approved drug lapatinib and a new experimental drug called a BET bromodomain inhibitor, which works by disrupting the expression of specific genes.

This study, a collaboration of 20 University of North Carolina researchers, is the first time a BET bromodomain inhibitor has been shown to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells.

“This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking,” said Gary Johnson, PhD, Kenan Distinguished Professor and chair of the department of pharmacology, a UNC Lineberger member, and senior author of the paper. “The combination treatments are currently being tested in different mouse models of breast cancer. Our goal is to create a new kind of therapy that could help oncologists make the response to treatment more durable and lasting for breast cancer patients.”

The HER2-positive subtype accounts for 15 to 20 percent of all breast cancer diagnoses. Only about one-third of these patients respond well to standard therapy. But even patients that initially respond eventually develop resistance. This is a universal problem of drugs that target specific proteins called kinases that drive tumor growth. Kinases are essential for cellular activities, such as movement, division, and signaling to other proteins to promote cell survival and growth. In this subtype of breast cancer, HER2 is the primary kinase involved in the growth of these tumors. When it’s blocked with a drug like lapatinib, cancer cells have ways to get around the roadblock by using other kinases.

Tim Stuhlmiller, PhD, a postdoctoral fellow in Johnson’s lab and first author of the paper, conducted experiments using a technique to determine kinase activity on a global scale throughout a group of given cells – a technology that Johnson’s lab had previously developed.

Stuhlmiller was able to see what happened to HER2-positive human cancer cells when treated with the HER2 inhibitor lapatinib. As expected, each cell line developed resistance to the drug. But, surprisingly, each cell line resisted in different ways. Not just one or two kinases activated to beat the lapatinib. Many kinases responded. And they were not the same kinases from cell line to cell line. But they did the same thing: they ensured that the cancer cells survived and grew.

“It was amazing,” Stuhlmiller said. “We found this massive up-regulation of many different kinases that could either reactivate the main HER2 signaling pathway or bypass it entirely. In fact, we discovered that nearly 20 percent of the cell’s entire gene expression profile was dysregulated when we treated the cells with lapatinib.”

Dysregulated genes lead to abnormal amounts of proteins. These proteins – the kinases – drive resistance to anti-cancer drugs. This research strongly suggests that there are many different ways HER2-positive cancer cells can compensate for the initial blockage of the HER2 protein. Thus, targeting all of these specific kinases would be extremely difficult.

“Because of toxicity concerns, you couldn’t inhibit all these kinases that potentially help cancer cells compensate in the face of a HER2 inhibitor,” Stuhlmiller said. “The more drugs you try to use, the more toxic that would be for patients and the lower the dose people would be able to tolerate.

“So that’s one take home message,” he said. “But the main message is we used a different kind of drug to block that entire massive kinase response before it ever happened.”

For that, Johnson’s team used a BET bromodomain inhibitor. It’s part of a new class of drugs that targets proteins involved in gene transcription – when particular parts of DNA are copied into RNA; this is the first step in the creation of enzymes, such as kinases.

Johnson’s team tested several BET bromodomain inhibitors, including one currently in clinical trials to treat blood cancers and a specific type of leukemia. During experiments, Johnson’s team found that BET bromodomain inhibitors targeted the gene transcription of most of the kinases responsible for resistance. By combining lapatinib with a BET bromodomain inhibitor, Stuhlmiller found that the HER2 kinase was blocked, as planned. Also, the massive kinase activation that typically followed HER2 inhibition never happened. The second drug suppressed the kinase response.

“We blocked it before it could happen,” Stuhlmiller said. “In all five cell lines we tested, there were no cancer cells left because the combination therapy blocked their growth. Essentially, we made the activity of lapatinib durable.” As a result, the cancer cells were annihilated.

Johnson’s lab and their UNC collaborators are currently working to replicate their findings in animal models of HER2-positive breast cancer. They think these types of combination therapies are going to be necessary to prevent resistance in the clinic. They’re also studying the effects of BET bromodomain inhibitors on other breast cancer subtypes, such as triple-negative breast cancer, another subtype that is difficult to treat.

Funding for this research was provided by the National Institutes of Health, the Susan G. Komen Foundation, and the University Cancer Research Fund at the University of North Carolina at Chapel Hill.

Other authors of the CELL Reports paper from the Johnson lab are graduate student Samantha Miller; and; research assistant professors Jon Zawistowski, PhD, Kazuhiro Nakamura, PhD, Adriana Beltran, PhD, and Steven Angus, PhD; research associate Noah Sciaky, PhD; research specialist Deborah Granger and research technician Rachel Reuther. Co-author James Duncan, PhD, was a postdoc in the Johnson lab during this research. He is now an assistant professor at the Fox Chase Cancer Center.

Other authors include Lee Graves, PhD, professor of pharmacology; Shelton Earp, MD, Lineberger Professor of Cancer Research and professor medicine and pharmacology; Shawn Gomez, EngScD, associate professor of biomedical engineering; Joel S. Parker, PhD, director of the Lineberger Bioinformatics Core; Lisa Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research; graduate student Kyla Collins; Jian Jin, PhD, adjunct associate professor at the UNC Eshelman School of Pharmacy and professor of oncological sciences at the Icahn School of Medicine at Mount Sinai in New York; Jin’s former lab member Xin Chen, PhD; and Pei-Fen Kuan, PhD, a former UNC biostatistician who is now an assistant professor at Stony Brook University.

]]>No publishergeneticscancer geneticsbreast cancer2015/04/09 15:40:00 GMT-4News ItemLower survival rates connected with high-risk melanoma with mutations, study findshttp://unclineberger.org/news/lower-survival-rates-connected-with-high-risk-melanoma-with-mutations-study-finds
A UNC Lineberger-led study found that people with higher-risk melanoma containing either BRAF or NRAS gene mutations had lower survival rates.Researchers from the UNC Lineberger Comprehensive Cancer Center led an analysis of hundreds of melanoma samples to find out if two genetic mutations more commonly found in melanoma tumors were associated with lower survival rates in patients.

In findings published in the journal JAMA Oncology on Thursday, the researchers reported that people with tumors containing either BRAF or NRAS gene mutations whose cancer was at a higher risk of spreading had lower survival rates. That was compared to when people with high-risk tumors lacking either mutation. The study was led by UNC Lineberger researchers, and involved scientists from around the world through the international, population-based Genes, Environment and Melanoma (GEM) Study.

“When you get to higher-risk, primary tumors, it looks like mutational status is associated with lower survival,” said Nancy E. Thomas, MD, PhD, a UNC Lineberger member, the Irene and Robert Alan Briggaman Distinguished Professor in the UNC School of Medicine Department of Dermatology and the study’s principal investigator. “These findings could help inform treatment decisions for patients, and highlights an area worth further study.”

Thomas said the researchers set out to do the study to find out if the BRAF and NRAS mutations could be used as indicators of patients’ prognosis. It was done at a critical period before new treatments were approved for melanoma – including before the first BRAF inhibitor was approved in 2011. So she said that means that the researchers were able look at outcomes connected with the mutations without the influence of those treatments.

“With these new medicines coming on board that have been shown to be relatively safe, I’m sure there’s going to be pressure to use the drugs earlier as adjuvant treatments,” Thomas said. “Our study tells us that certain patients might be at higher risk, and might be better candidates for treatment.”

For the study, the researchers followed 912 melanoma patients for seven years. The patients were all diagnosed in 2000, and were enrolled through the GEM study. Thirteen percent had tumors with NRAS mutations, 30 percent had BRAF mutations, and 57 percent had neither.

Overall, they found there was no statistically significant difference in the five-year survival rates for people with NRAS or BRAF-mutated melanoma tumors compared with survival in people with tumors lacking mutations. However, the researchers did find lower five-year survival rates in people with higher-risk tumors with mutations.

Specifically, they found that 73 percent of people with high-risk, NRAS-mutated tumors survived five years and 71 percent of people with high-risk tumors with BRAF mutations survived five years. That was compared with a five-year survival rate of 82 percent for people with high-risk cancer and lacking either mutation.

Kathleen Dorsey, a UNC Lineberger member, an assistant professor of cancer epidemiology in the UNC School of Medicine and a study co-author, said the findings may have clinical implications for people with the mutations and higher-risk cancer.

“We found an approximately three-fold increased risk of death from NRAS+ and BRAF+ mutations that was limited to higher-stage tumors,” she said. “This finding could be useful in identifying patients at high risk of death from melanoma based on their mutational status and primary melanoma tumor characteristics. Mutational status could also be important for determining eligibility for adjuvant trials.”

In addition to tracking survival, the researchers also examined characteristics of the tumors. They looked for indicators of tumor growth and at markers of the immune system’s response to the cancer.

In tumors with mutations in the NRAS gene, they found a lower number of lymphocytes in and around the cancer cells. Lymphocytes are a type of white blood cell that can help fight cancer and other diseases.

“One of the major findings of this study is that melanomas with a mutation in the NRAS gene have fewer tumor-infiltrating lymphocytes,” Thomas said. “That’s important because of the new immunotherapies that require infiltrating lymphocytes to be present in order for the treatments to work.”

This research was supported by National Cancer Institute grants, the National Institute of Environmental health Sciences, and the University of Sydney Medical Foundation Program grant.

]]>No publishermelanomacancer geneticsgeneticssurvivorship2015/04/09 11:05:00 GMT-4News ItemUNC Lineberger sequences 10,000 tumors as part of national cancer genomics efforthttp://unclineberger.org/news/10k-tumors
UNC sequenced the RNA for 10,000 tumor samples as part of The Cancer Genome Atlas project, a National Cancer Institute and National Human Genome Research Institute-backed effort to create a comprehensive atlas of the genetic changes in cancer.The UNC Lineberger Comprehensive Cancer Center is leading a national, multi-year, collaborative effort to characterize the genetic changes in nearly 30 cancer types. Earlier this year, UNC Lineberger hit a milestone in this effort – sequencing 10,000 samples of cancer tumor tissue.

UNC sequenced the RNA for 10,000 tumor samples as part of The Cancer Genome Atlas project, a National Cancer Institute and National Human Genome Research Institute-backed effort to create a comprehensive atlas of the genetic changes in cancer.

The work helped lay the foundation for groundbreaking research completed as part of TCGA. And with approximately 10,000 of the samples sequenced by UNC uploaded to a public database accessible to researchers around the world, the work is expected to continue to fuel new discoveries.

“We expect that the data that UNC gathered for this large-scale sequencing project will be an active discovery resource that scientists use to discover new things for at least another decade, and potentially for more,” said D. Neil Hayes, MD, MPH, a UNC Lineberger member and an associate professor of clinical research in hematology and oncology at the UNC School of Medicine.

UNC was able to hit the milestone because of key investments in next-generation sequencing technology, Hayes said, as well as because it had the staff to operate that technology and the leadership of key scientific investigators.

“No. 1, it was scientific leadership that made this project possible, and No. 2, it was production capacity,” Hayes said. “We had to have the resources to be able to handle roughly 200 samples a month on the sequencing side and on the analytics side, as well as storage space, sequencers, computers, project management expertise – and many of these things were supported by cancer center resources and the state of North Carolina.”

Investments in next-generation sequencing technology from the state-funded University Cancer Research Fund were “crucial,” said Piotr Mieczkowski, director of UNC’s High Throughput Sequencing Facility and a research assistant professor of genetics. The University Cancer Research Fund helped UNC to buy faster, more efficient sequencers.

“You have to remember that when everything was happening, next-generation sequencing technology was really very, very new,” Mieczkowski said. “In just a few years, we have built real knowledge of how to create various types of libraries and how to perform sequencing on a large scale.”

Specifically, the major piece of the work that UNC did to support the project was to sequence RNA, which is the genetic code that carries instructions from DNA for making proteins. Sequencing of RNA allows for researchers to get a more detailed look at how genes are expressed in cancer cells, said Katherine Hoadley, PhD, a UNC Lineberger member and research assistant professor in genetics. And she said gene expression analysis has been shown to be “incredibly useful” in classifying multiple tumor types by their molecular characteristics.

“What set the TCGA project apart from similar genomic projects is that we actually had six different, very diverse and broad-reaching genome analysis technologies that we could use to study tumors’ molecular characteristics,” said Charles M. Perou, PhD, a UNC Lineberger member and professor of genetics and pathology in the UNC School of Medicine. “By handling much of the project’s RNA sequencing, UNC played a major role in making that comprehensive approach to the genetic characterization of tumors possible.”

TCGA has resulted in multiple publications and findings, with 10 studies in the journal Nature, three in the journal Cancer Cell, and three in the journal Cell. UNC researchers played prominent roles in all of these studies, including being the lead site for TCGA studies of breast cancer and glioblastoma, the most common form of malignant brain cancer in adults. Perou and Hoadley led a recent study published in Cell that pointed to a new molecular classification for cancers. For that paper, the researchers studied 12 different tumor types at once.

The research that the sequencing helped to inform as part of TCGA helped push the field of cancer genomics to the next level, Hayes said.

“Before, there was always the promise of sequencing – that it could do this, it might reveal that,” Hayes said. “And although not all the data is analyzed yet from this effort, I think we’ve moved past the theoretical questions about what we might find, and into a much more real state of here is what the cancer genome looks like.”

And while the production side of the project is done, Hoadley said researchers plan to continue to use the data for further analysis. In addition, said the TCGA model is expected to be used for future collaborative cancer research projects. Major findings from TCGA will be reviewed at an upcoming symposium to be hosted by UNC Lineberger April 8-9 at The William and Ida Friday Center for Continuing Education.

About UNC Lineberger

One of only 41 NCI-designated comprehensive cancer centers, the University of North Carolina Lineberger Comprehensive Cancer Center brings together some of the most exceptional physicians and scientists in the country to investigate and improve the prevention, early detection and treatment of cancer. With research that spans the spectrum from the laboratory to the bedside to the community, UNC Lineberger faculty work to understand the causes of cancer at the genetic and environmental levels, to conduct groundbreaking laboratory research, and to translate findings into pioneering and innovative clinical trials. For more information, please visit www.unclineberger.org.

]]>No publisherucrfcancer geneticstcga2015/03/31 12:20:00 GMT-4News ItemAll the Cell’s a Stagehttp://unclineberger.org/news/all-the-cell2019s-a-stage
Brian Strahl, PhD, and his band of biochemists unravel the complicated mysteries of the epigenetic code to find a culprit in cancer development.Every single human cell contains every single human gene. But depending on the cell, only some of these genes need to be expressed or “turned on.” For instance, a heart cell has all the genes needed for, say, proper kidney function. But that heart cell won’t express those genes. In a heart cell, those genes are “turned off.” When one of these “wrong” genes is turned on by mistake, the result can be rampant cell growth – cancer.

How this happens used to be the stuff of science fiction. Now, scientists know that there are tiny proteins –epigenetic proteins - that sit atop the genetic code inside cells. These proteins are responsible for turning on or off the genes.

Now, UNC researchers discovered that one gene-regulating protein called Bre1 must be maintained in the proper amount for other epigenetic players to do their jobs properly. It’s a key coordinator in the sort of cellular scenes that can turn a healthy cell into a cancer cell.

Setting the scene

Within each cell of the body is an ongoing and intricate performance with genes playing some of the leading roles. As with all performances, the actors do not act alone, but instead, rely on support from behind the scenes. This supporting staff provides the script and cues for what the genes are supposed to say and do – how genes are accessed and used. Important members of the support staff are histones – the proteins that package genes inside cells and allow them to be used for various cellular functions that keep us healthy; they allow the plot to unfold perfectly.

Unfortunately, sometimes cues are missed or lines are forgotten and the show doesn’t go as planned. This causes the actors to speak when they should be quiet or stay quiet when they should speak. And if one of these actor genes happens to be essential for, say, cell growth, then the result can be disastrous. The actors take the story in an unintended direction.

All this supporting staff is part of epigenetics – epi meaning on or above – a field that focuses on the environment and the players that allow our genes to act.

“I think epigenetics is a new frontier of cancer research,” says Brian Strahl, Ph.D., a professor of biochemistry and biophysics in the UNC School of Medicine. “We can now sequence the entire genome of a cancer cell, and what we’re finding is that many cancers have mutations in the epigenetic machinery. We’re not just finding this in cancer cell lines in the lab but in cancer patients.”

The director’s cut

Strahl, who’s a member of the UNC Lineberger Comprehensive Cancer Center, said major questions surround how histones wrap up the DNA into chromatin – a structure that allows or denies access to the genetic information inside our cells.

This is what Strahl studies. His goal is to figure out precisely how histones contribute to basic biological functions and, in turn, contribute to cancers and other diseases. Adding a twist to this idea, however, is the fact that not every histone is the same.

“We’ve already learned that the histone proteins found at the sites of genes can be chemically modified with a variety of small chemical “tags” that either promote or further prevent access to our genetic information – our DNA. And this access or denial ultimately affects genes so they are either activated or not.”

These chemical tags come from a variety of sources – mainly the food we eat, the chemicals in the environment that gets inside us through our skin and lungs, for example, and the various biological chemicals that simply make us tick. Proper nutrients, for instance, allow for the formation of chemical tags to direct the histones to activate genes in the proper ways. Nasty environmental stuff, such as cigarette smoke, can mess up the epigenetic machinery.

Yet, these chemical tags are not ultimately in charge of the genes. Another layer of proteins above the histones are responsible for putting on the chemical tags.

“Something has to ensure that these chemical tags on histones are regulated properly, to ensure that the tags are only present on the right genes at the right time,” Strahl said.

Strahl and graduate student Glenn Wozniak focused on one of the proteins that add these chemical tags – a protein called Bre1, which keeps one tag – ubiquitin – in check.

In a sense, Bre1 hires ubiquitin; it allows ubiquitin to do its job.

Ubiquitin is known to help a histone open up the cell’s chromatin to expose genes for activation. When ubiquitin is finished, it is removed from the histones, and the genes become inactivated.

If this process goes awry – if the genes are allowed to remain active indefinitely – then normal cells can turn into cancer cells. And the entire cellular performance collapses.

The Goldilocks effect

Until now, how this happened was unclear. Through a series of experiments, Strahl and Wozniak found that, like the chemical tags themselves, a precise amount of Bre1 must be maintained to ensure that just the right amount of ubiquitin is added to histones.

Wozniak added, “We also found that when Bre1 is not needed or when it doesn’t perform its function, it’s removed as a control mechanism. There won’t be as much ubiquitin on histones because Bre1 is not there.”

Strahl and Wozniak’s finding illuminates what had been an epigenetic mystery. Scientific literature on Bre1 had been mixed.

“Some studies indicated that Bre1 had a role as a tumor suppressor,” Strahl said. “Other studies showed that it’s a cancer promoter. So there’s been conflicting evidence about all of this. Now we know. If there’s too little Bre1, the gene won’t turn on.” This could turn off the genes that protect the cell from cancer. “If there’s too much,” Strahl said. “Then the genes might not turn off.” This could also trigger cancer development.

“When you think about it, Bre1 could be a really good target for a cancer drug,” Strahl said. “Cancer cells divide rapidly. A lot of chemotherapies involve creating DNA damage within all rapidly dividing cells. But if you just target the Bre1 protein and maybe shut it off, you could have very bad outcomes specifically for rapidly dividing cancer cells. They wouldn’t be able to transcribe genes anymore.”

Strahl and Wozniak’s study appeared in the journal Genes and Development. The National Science Foundation funded this work.

]]>No publisher2014cancer genetics2014/10/10 15:10:00 GMT-4News ItemUNC researchers find final pieces to the circadian clock puzzlehttp://unclineberger.org/news/unc-researchers-find-final-pieces-to-the-circadian-clock-puzzle
Sixteen years after scientists found the genes that control the circadian clock in all cells, the lab of UNC’s Aziz Sancar, MD, PhD, discovered the mechanisms responsible for keeping the clock in sync.CHAPEL HILL, NC – Researchers at the UNC School of Medicine have discovered how two genes – Period and Cryptochrome – keep the circadian clocks in all human cells in time and in proper rhythm with the 24-hour day, as well as the seasons. The finding, published today in the journal Genes and Development, has implications for the development of drugs for various diseases such as cancers and diabetes, as well as conditions such as metabolic syndrome, insomnia, seasonal affective disorder, obesity, and even jetlag.

“Discovering how these circadian clock genes interact has been a long-time coming,” said Aziz Sancar, MD, PhD, Sarah Graham Kenan Professor of Biochemistry and Biophysics and senior author of the Genes and Development paper. “We’ve known for a while that four proteins were involved in generating daily rhythmicity but not exactly what they did. Now we know how the clock is reset in all cells. So we have a better idea of what to expect if we target these proteins with therapeutics.”

In all human cells, there are four genes – Cryptochrome, Period, CLOCK, and BMAL1 – that work in unison to control the cyclical changes in human physiology, such as blood pressure, body temperature, and rest-sleep cycles. The way in which these genes control physiology helps prepare us for the day. This is called the circadian clock. It keeps us in proper physiological rhythm. When we try to fast-forward or rewind the natural 24-hour day, such as when we fly seven time zones away, our circadian clocks don’t let us off easy; the genes and proteins need time to adjust. Jetlag is the feeling of our cells “realigning” to their new environment and the new starting point of a solar day.

Previously, scientists found that CLOCK and BMAL1 work in tandem to kick start the circadian clock. These genes bind to many other genes and turn them on to express proteins. This allows cells, such as brain cells, to behave the way we need them to at the start of a day.

Specifically, CLOCK and BMAL1 bind to a pair of genes called Period and Cryptochrome and turn them on to express proteins, which – after several modifications – wind up suppressing CLOCK and BMAL1 activity. Then, the Period and Cryptochrome proteins are degraded, allowing for the circadian clock to begin again.

“It’s a feedback loop,” said Sancar, who discovered Cryptochrome in 1998. “The inhibition takes 24 hours. This is why we can see gene activity go up and then down throughout the day.”

But scientists didn’t know exactly how that gene suppression and protein degradation happened at the back end. In fact, during experiments using one compound to stifle Cryptochrome and another drug to hinder Period, other researchers found inconsistent effects on the circadian clock, suggesting that Cryptochrome and Period did not have the same role. Sancar, a member of the UNC Lineberger Comprehensive Cancer Center who studies DNA repair in addition to the circadian clock, thought the two genes might have complementary roles. His team conducted experiments to find out.

Chris Selby, PhD, a research instructor in Sancar’s lab, used two different kinds of genetics techniques to create the first-ever cell line that lacked both Cryptochrome and Period. (Each cell has two versions of each gene. Selby knocked out all four copies.)

Then Rui Ye, PhD, a postdoctoral fellow in Sancar’s lab and first author of the Genes and Development paper, put Periodback into the new mutant cells. But Period by itself did not inhibit CLOCK-BMAL1; it actually had no active function inside the cells.

Next, Ye put Cryptochrome alone back into the cell line. He found that Cryptochrome not only suppressed CLOCK and BMAL1, but it squashed them indefinitely.

For the final experiment, Sancar’s team added Period to the cells with Cryptochrome. As Period’s protein accumulated inside cells, the scientists could see that it began to remove the Cryptochrome, as well as CLOCK and BMAL1. This led to the eventual degradation of Cryptochrome,and then the CLOCK-BMAL1 genes were free to restart the circadian clock anew to complete the 24-hour cycle.

“What we’ve done is show how the entire clock really works,” Sancar said. “Now, when we screen for drugs that target these proteins, we know to expect different outcomes and why we get those outcomes. Whether it’s for treatment of jetlag or seasonal affective disorder or for controlling and optimizing cancer treatments, we had to know exactly how this clock worked.”

Previous to this research, in 2010, Sancar’s lab found that the level of an enzyme called XPA increased and decreased in synchrony with the circadian clock’s natural oscillations throughout the day. Sancar’s team proposed that chemotherapy would be most effective when XPA is at its lowest level. For humans, that’s late in the afternoon.

“This means that DNA repair is controlled by the circadian clock,” Sancar said. “It also means that the circadian clocks in cancer cells could become targets for cancer drugs in order to make other therapeutics more effective.”

This research was funded by the National Institutes of Health and the Science Research Council and Academia Sinica in Taiwan.

Other authors of the Genes and Development paper are UNC postdoctoral fellows Yi-Ying Chiou, PhD, and Shobban Gaddameedhi, PhD, and UNC graduate student Irem Ozkan-Dagliyan.

]]>No publisher2014cancer genetics2014/09/16 14:45:00 GMT-4News ItemMauro Calabresehttp://unclineberger.org/people/mauro-calabrese
PhD, Assistant Professor, UNC-Chapel Hill, Cancer GeneticsNo publishercancer genetics2014/08/25 10:14:00 GMT-4PersonLargest cancer genetic analysis reveals new way of classifying cancer http://unclineberger.org/news/classifying-cancer
Researchers with The Cancer Genome Atlas (TCGA) Research Network have completed the largest, most diverse tumor genetic analysis ever conducted, revealing a new approach to classifying cancers. The work, led by researchers at the UNC Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and other TCGA sites, not only revamps traditional ideas of how cancers are diagnosed and treated, but could also have a profound impact on the future landscape of drug development. “We found that one in ten cancers analyzed in this study would be classified differently using this new approach,” said Chuck Perou, Ph.D., professor of genetics and pathology, UNC Lineberger member and senior author of the paper, which appears online Aug. 7 in Cell. “That means that ten percent of the patients might be better off getting a different therapy – that’s huge.”

Since 2006, much of the research has identified cancer as not a single disease, but many types and subtypes and has defined these disease types based on the tissue – breast, lung, colon, etc. – in which it originated. In this scenario, treatments were tailored to which tissue was affected, but questions have always existed because some treatments work, and fail for others, even when a single tissue type is tested.

In their work, TCGA researchers analyzed more than 3,500 tumors across 12 different tissue types to see how they compared to one another -- the largest data set of tumor genomics ever assembled, explained Katherine Hoadley, Ph.D., research assistant professor in genetics and lead author. They found that cancers are more likely to be genetically similar based on the type of cell in which the cancer originated, compared to the type of tissue in which it originated.

“In some cases, the cells in the tissue from which the tumor originates are the same,” said Hoadley. “But in other cases, the tissue in which the cancer originates is made up of multiple types of cells that can each give rise to tumors. Understanding the cell in which the cancer originates appears to be very important in determining the subtype of a tumor and, in turn, how that tumor behaves and how it should be treated.”

Perou and Hoadley explain that the new approach may also shift how cancer drugs are developed, focusing more on the development of drugs targeting larger groups of cancers with genomic similarities, as opposed to a single tumor type as they are currently developed.

One striking example of the genetic differences within a single tissue type is breast cancer. The breast, a highly complex organ with multiple types of cells, gives rise to multiple types of breast cancer; luminal A, luminal B, HER2-enriched and basal-like, which was previously known. In this analysis, the basal-like breast cancers looked more like ovarian cancer and cancers of a squamous-cell type origin, a type of cell that composes the lower-layer of a tissue, rather than other cancers that arise in the breast.

“This latest research further solidifies that basal-like breast cancer is an entirely unique disease and is completely distinct from other types of breast cancer,” said Perou. In addition, bladder cancers were also quite diverse and might represent at least three different disease types that also showed differences in patient survival.

As part of the Alliance for Clinical Trials in Oncology, a national network of researchers conducting clinical trials, UNC researchers are already testing the effectiveness of carboplatin – a common treatment for ovarian cancer – on top of standard of care chemotherapy for triple-negative breast cancer (TNBC) patients, of which 80 percent are the basal-like subtype. The results of this study (called CALGB40603) were just published on Aug. 6 in the Journal of Clinical Oncology and showed a benefit of carboplatin in TNBC patients. This new clinical trial result suggests that there may be great value in comparing clinical results across tumor types for which this study highlights as having common genomic similarities.

As participants in TCGA, UNC Lineberger scientists have been involved in multiple individual tissue type studies including most recently an analysis of a comprehensive genomic profile of lung adenocarcinoma. Perou’s seminal work in 2000 led to the first discovery of breast cancer as not one, but in fact, four distinct subtypes of disease. These most recent findings should continue to lay the groundwork for what could be the next generation of cancer diagnostics.

About The Cancer Genome Atlas (TCGA) Research Network

TCGA is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health. TCGA-generated data are freely available in advance of publication at the TCGA Data Portal, http://tcga-data.nci.nih.gov/tcga, and CGHub, https://cghub.ucsc.edu.

The TCGA Research Network includes more than 150 researchers at dozens of institutions across the nation. A list of participants is available athttp://cancergenome.nih.gov/abouttcga/overview. More details about TCGA, including Quick Facts, Q&A, graphics, glossary, a brief guide to genomics and a media library of images can be found at http://cancergenome.nih.gov.

About UNC Lineberger

One of only 41 NCI-designated comprehensive cancer centers, the University of North Carolina Lineberger Comprehensive Cancer Center brings together some of the most exceptional physicians and scientists in the country to investigate and improve the prevention, early detection and treatment of cancer. With research that spans the spectrum from the laboratory to the bedside to the community, UNC Lineberger faculty work to understand the causes of cancer at the genetic and environmental levels, to conduct groundbreaking laboratory research, and to translate findings into pioneering and innovative clinical trials. For more information, please visit www.unclineberger.org.